Activitating TRAIL death receptors with human agonist monoclonal antibodies Free

SY13-01

The cell surface receptors for Tumor Necrosis Factor Related Apoptosis-Inducing Ligand (TRAIL) are expressed on a majority of human tumor cells. Binding of agonistic monoclonal antibodies (mAbs) or the ligand TRAIL, to either functional death receptor, TRAIL-R1 or TRAIL-R2, rapidly induces the activation of a protease-mediated signaling cascade that culminates in programmed cell death. The predominantly tumor-restricted pattern of receptor expression and the ability to induce tumor cell death with receptor agonists make the TRAIL-R pathway an attractive target for cancer therapeutic agents.

We have developed fully human, IgG₁, monoclonal antibodies, mapatumumab and lexatumumab, that specifically bind either TRAIL-R1 or TRAIL-R2, respectively and activate the apoptotic pathway in tumor cells. Preclinical evaluation of these agonistic TRAIL-R mAbs demonstrated rapid activation of the cell death cascade, increased cytotoxicity and potent induction of apoptosis across a broad range of human tumor cell lines and primary cells from both solid and hematologic malignancies. Treatment of tumor cell xenografts elicited significant inhibition of tumor growth including rapid tumor regression in sensitive models.

The TRAIL-R mAbs were active in combination with a spectrum of conventional or novel therapeutic agents including chemotherapy, radiation and proteosome inhibitors. Combination treatment increased the number of responsive tumor cell lines, levels of apoptosis and induced significant tumor growth inhibition including synergistic anti-tumor activity and tumor regression in xenograft models.

Apoptosis is regulated at several checkpoints in the signaling cascade. Key mechanisms and proteins have been obstructed or altered by the cancer cell thereby increasing the apoptotic threshold. We and our collaborators have been exploring the ability of targeted therapy to modify the anti-apoptotic threshold of tumor cells and complement the ability of the TRAIL-R mAbs to trigger apoptosis. The combination of TRAIL receptor activation with TRAIL-R mAbs and attenuation of the anti-apoptotic threshold with targeted molecular therapy holds promise as a novel and rational approach to cancer treatment.

Several human monoclonal antibodies and a recombinant TRAIL ligand have advanced through preclinical assessment and are now in the clinic. Mapatumumab and lexatumumab, which target TRAIL-R1 or TRAIL-R2 respectively, are currently being evaluated in clinical trials in a variety of human tumors. Agonism of the TRAIL-R pathway represents a novel and promising avenue for selective targeting and elimination of the tumor cell.